The present invention relates to quinoline derivatives, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability and to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi""s sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of VEGF action by sequestration of VEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Flt or Flt1, the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Flt and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
European Patent Publication No. 0326330 discloses certain quinoline, quinazoline and cinnoline plant fungicides. Certain of these plant fungicides are also stated to possess insecticidal and miticidal activity. There is however no disclosure or any suggestion that any of the compounds disclosed may be used for any purpose in animals such as humans. In particular, the European Patent Publication contains no teaching whatsoever concerning angiogenesis and/or increased vascular permeability mediated by growth factors such as VEGF.
The present invention is based on the surprising discovery that certain quinolines inhibit the effects of VEGF, a property of value in the treatment of disease states associated with angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi""s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation. Compounds of the present invention possess good activity against VEGF receptor tyrosine kinase whilst possessing some activity against epidermal growth factor (EGF) receptor tyrosine kinase. Furthermore, compounds of the present invention, possess substantially higher potency against VEGF receptor tyrosine kinase than against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase. Thus compounds of the invention which have been tested possess activity against VEGF receptor tyrosine kinase such that they may be used in an amount sufficient to inhibit VEGF receptor tyrosine kinase whilst demonstrating no significant activity against EGF receptor tyrosine kinase or FGF R1 receptor tyrosine kinase.
According to one aspect of the present invention there is provided the use of compounds of the formula I: 
[wherein:
R2 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
n is an integer from 0 to 5;
Z represents xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH2xe2x80x94;
G1 represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group containing 1 to 3 heteroatoms selected from O, S and N;
Y1, Y2, Y3 and Y4 each independently represents carbon or nitrogen with the proviso that Y1, Y2, Y3 and Y4 are not all nitrogen;
R1 represents fluoro or hydrogen;
m is an integer from 1 to 3;
R3 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, xe2x80x94NR4R5 (wherein R4 and R5, which may be the same or different, each represents hydrogen or C1-3alkyl), or a group R6xe2x80x94X1xe2x80x94 wherein X1 represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94OCOxe2x80x94, carbonyl, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94SO2NR9xe2x80x94, xe2x80x94NR10SO2xe2x80x94 or xe2x80x94NR11xe2x80x94 (wherein R7, R8, R9, R10 and R11 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R6 is selected from one of the following sixteen groups:
1) C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;
2) C1-5alkylX2COR2 (wherein X2 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR13xe2x80x94 (wherein R13 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R12 represents xe2x80x94NR14R15xe2x80x94 or xe2x80x94OR16xe2x80x94 (wherein R14, R15 and R16 which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl));
3) C1-5alkylX3R17 (wherein X3 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94NR18COxe2x80x94, xe2x80x94CONR19xe2x80x94, xe2x80x94SO2NR20xe2x80x94, xe2x80x94NR21SO2xe2x80x94 or xe2x80x94NR22xe2x80x94 (wherein R18, R19, R20, R21 and R22 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R17 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-3alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
4) C1-5alkylX4C1-5alkylX5R23 (wherein X4 and X5 which may be the same or different are each xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR24COxe2x80x94, xe2x80x94CONR25xe2x80x94, xe2x80x94SO2NR26xe2x80x94, xe2x80x94NR27SO2xe2x80x94 or xe2x80x94NR28xe2x80x94 (where R24, R25, R26, R27 and R28 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R23 represents hydrogen or C1-3alkyl);
5) C1-5alkylR29 (wherein R29 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
6) (CH2)qX6R30 (wherein q is an integer from 0 to 5, X6 represents a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR31COxe2x80x94, xe2x80x94CONR32xe2x80x94, xe2x80x94SO2NR33xe2x80x94, xe2x80x94NR34SO2xe2x80x94 or xe2x80x94NR35xe2x80x94 (wherein R31, R32, R34 and R35 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4hydroxyalkoxy, C1-4aminoalkyl, C1-4alkylamino, carboxy, cyano, xe2x80x94CONR36R37 and xe2x80x94NR38COR39 (wherein R36, R37, R38 and R39, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
7) C2-6alkenylR29 (wherein R29 is as defined hereinbefore);
8) C2-6alkynylR29 (wherein R29 is as defined hereinbefore);
9) X7R40 (wherein X7 is xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94CONR41R42xe2x80x94 (wherein R41 and R42, which same or different, each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R40 represents C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the provisos that when X7 is xe2x80x94SO2xe2x80x94, X1 is xe2x80x94Oxe2x80x94, when X7 is xe2x80x94Oxe2x80x94, X1 is carbonyl, when X7 is xe2x80x94CONR41R42xe2x80x94, X1 is xe2x80x94Oxe2x80x94 or NR11 (wherein R41, R42 and R11 are as defined hereinbefore);
10) C2-6alkenylR30 (wherein R30 is as defined hereinbefore);
11) C2-6alkynylR30 (wherein R30 is as defined hereinbefore);
12) C2-6alkenylX8R30 (wherein X8 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR43COxe2x80x94, xe2x80x94CONR44xe2x80x94, xe2x80x94SO2NR45xe2x80x94, xe2x80x94NR46SO2xe2x80x94 or xe2x80x94NR47xe2x80x94 (wherein R43, R44, R45, R46 and R47 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 is as defined hereinbefore);
13) C2-6alkynylX9R30 (wherein X9 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR48COxe2x80x94, xe2x80x94CONR49xe2x80x94, xe2x80x94SO2NR50xe2x80x94, xe2x80x94NR51SO2xe2x80x94 or xe2x80x94NR52xe2x80x94 (wherein R48, R49, R50, R51 and R52 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 is as defined hereinbefore);
14) C1-3alkylX10C1-3alkylR30 (wherein X10 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR53COxe2x80x94, xe2x80x94CONR54xe2x80x94, xe2x80x94SO2NR55xe2x80x94, xe2x80x94NR56SO2xe2x80x94 or xe2x80x94NR57xe2x80x94 (wherein R53, R54, R55, R56 and R57 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 is as defined hereinbefore);
15) R29 (wherein R29 is as defined hereinbefore); and
16) C1-3alkylX10C1-3alkylR29 (wherein X10 and R29 are as defined hereinbefore);] and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
In one embodiment of the present invention R2 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro, preferably hydroxy, halogeno or C1-2alkyl, especially hydroxy or halogeno.
In another embodiment of the present invention one R2 is conveniently hydroxy, but advantageously one R2 substituent is meta-hydroxy and the other one or more are each selected from halogeno, methyl and methoxy.
In another embodiment of the invention the phenyl group bearing (R2)n is preferably of the formula II: 
wherein:
Ra represents hydrogen, methyl, fluoro or chloro, preferably hydrogen, fluoro or chloro, especially fluoro;
Rb represents hydrogen, methyl, methoxy, cyano, bromo, fluoro or chloro;
Rc represents hydrogen or hydroxy, especially hydroxy;
Rd represents hydrogen, fluoro or chloro, especially hydrogen or fluoro.
Preferably in another embodiment of the invention two R2 substituents are halogeno, and the other one or more are each selected from halogeno, hydroxy and methyl.
In a particular aspect of the present invention, the phenyl group bearing (R2)n is the 2-fluoro-5-hydroxy-4-methylphenyl group, the 4-chloro-2-fluoro-5-hydroxyphenyl group, the 4-bromo-2-fluoro-5-hydroxyphenyl group, the 3-hydroxy-4-methylphenyl group, the 3-hydroxyphenyl group or the 4-chloro-2-fluorophenyl group.
More especially the phenyl group bearing (R2)n is the 2-fluoro-5-hydroxy-4-methylphenyl group, the 4-chloro-2-fluoro-5-hydroxyphenyl group or the 4-chloro-2-fluorophenyl group.
Preferably n is an integer from 1 to 3, more preferably n is 2 or 3.
Preferably Z represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, but especially xe2x80x94NHxe2x80x94.
Advantageously G1 represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group containing 1 to 3 nitrogen atoms.
Preferably G1 represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group containing 1 to 2 nitrogen atoms.
More preferably G1 represents phenyl.
Advantageously two of Y1, Y2, Y3 and Y4 each represent carbon and two each represent nitrogen, or only one of Y1, Y2, Y3 and Y4 represents nitrogen and the other three each represent carbon, or each of Y1, Y2, Y3 and Y4 represents carbon.
Preferably only one of Y1, Y2, Y3 and Y4 represents nitrogen and the other three each represent carbon, or each of Y1, Y2, Y3 and Y4 represents carbon.
More preferably each of Y1, Y2, Y3 and Y4 represents carbon.
Preferably R1 represents hydrogen.
Preferably m is an integer from 1 to 2.
Advantageously X1 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR10SO2xe2x80x94 or xe2x80x94NR11xe2x80x94 (wherein R7, R10 and
R11 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X1 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR7COxe2x80x94, xe2x80x94NR10SO2xe2x80x94 (wherein R7 and R10 each independently represents hydrogen or C1-2alkyl) or NH.
More preferably X1 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR7COxe2x80x94 (wherein R7 represents hydrogen or C1-2alkyl) or NH.
Particularly X1 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR7COxe2x80x94 (wherein R7 represents hydrogen or C1-2alkyl), more particularly xe2x80x94Oxe2x80x94 or xe2x80x94NHCOxe2x80x94, especially xe2x80x94Oxe2x80x94.
Advantageously X2 represents xe2x80x94Oxe2x80x94 or NR13 (wherein R13 represents hydrogen, C1-3alkyl or C1-2alkoxyethyl).
Advantageously X3 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR18COxe2x80x94, xe2x80x94NR21SO2xe2x80x94 or xe2x80x94NR22xe2x80x94 (wherein R18, R21 and R22 each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X3 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR22xe2x80x94 (wherein R22 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
More preferably X3 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR2xe2x80x94 (wherein R22 represents hydrogen or C1-2alkyl).
Advantageously X4 and X5 which may be the same or different each represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR28xe2x80x94 (wherein R28 represents hydrogen C1-3alkyl or C1-2alkoxyethyl).
Preferably X4 and X5 which may be the same or different each represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR28xe2x80x94 (wherein R28 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
More preferably X4 and X5 which may be the sane or different each represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94.
Advantageously X6 represents a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NR34SO2 or xe2x80x94NR35xe2x80x94 (wherein R35 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X6 represents a direct bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR35xe2x80x94 (wherein R35 represents hydrogen or C1-2alkyl).
More preferably X6 represents a direct bond.
Preferably X7 represents SO2 or xe2x80x94CONR41R42xe2x80x94 with the provisos that when X7 is xe2x80x94SO2xe2x80x94, X1 is xe2x80x94Oxe2x80x94, when X7 is xe2x80x94CONR41R42xe2x80x94, X1 is xe2x80x94Oxe2x80x94 or NR11 (wherein R41, R42 and R11 are as defined hereinbefore).
Advantageously X8 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR47xe2x80x94 (wherein R47 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X8 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR47xe2x80x94 (wherein R47 represents hydrogen or C1-2alkyl).
Advantageously X9 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR52xe2x80x94 (wherein R52 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X9 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR52xe2x80x94 (wherein R52 represents hydrogen or C1-2alkyl).
Advantageously X10 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR57xe2x80x94 (wherein R57 represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X10 represents xe2x80x94Oxe2x80x94 or xe2x80x94NR57xe2x80x94 (wherein R57 represents hydrogen or C1-2alkyl).
R29 is preferably pyrrolidinyl, piperazinyl, piperidinyl, morpholino or thiomorpholino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy.
Where R30 is a 5 or 6-membered aromatic heterocyclic group, it preferably has 1 or 2 heteroatoms, selected from O, N and S, of which more preferably one is N, and may be substituted as hereinbefore defined.
R30 is particularly a phenyl, pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group which group may be substituted as hereinbefore defined, more particularly a phenyl, pyridone, pyridyl, imidazolyl, thiazolyl or triazolyl group, especially a phenyl, pyridyl, thiazolyl, imidazolyl or triazolyl group which group may be substituted as hereinbefore defined.
In one embodiment of the invention R30 represents a pyridone, phenyl or 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which group may preferably carry up to 2 substituents, more preferably up to one substituent, selected from the group of substituents as hereinbefore defined.
In the definition of R30, conveniently substituents are selected from halogeno, C1-4alkyl, C1-4alkoxy and cyano, more conveniently substituents are selected from chloro, fluoro, methyl and ethyl.
Conveniently R3 represents halogeno, cyano, nitro, trifluoromethyl or a group R6xe2x80x94X1xe2x80x94 (wherein R6 and X1 are as defined hereinbefore).
Advantageously R3 represents chloro, cyano, nitro, trifluoromethyl or a group R6xe2x80x94X1xe2x80x94 (wherein R6 and X1 are as defined hereinbefore).
Conveniently R6 is selected from one of the following sixteen groups:
1) C1-5alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3alkylX2COR12 (wherein X2 is as defined hereinbefore and R12 represents xe2x80x94NR14R15xe2x80x94 or OR16xe2x80x94 (wherein R14, R15 and R16 which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-4alkylX3R17 (wherein X3 is as defined hereinbefore and R17 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-3alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
4) C2-3alkylX4C2-3alkylX5R23 (wherein X4 and X5 are as defined hereinbefore and R23 represents hydrogen or C1-3alkyl);
5) C1-5alkylR58 (wherein R58 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy) or C2-5alkylR59 (wherein R59 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C2-5alkyl through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
6) (CH2)qX6R30 (wherein X6 is as defined hereinbefore; q is an integer from 0 to 4 if X6 is a direct bond and q is 0, 2 or 3 if X6 is other than a direct bond; and R30 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, advantageously substituted with up to 2 substituents as hereinbefore defined, more preferably substituted with one substituent selected from the group of substituents as hereinbefore defined);
7) C4-5alkenylR60 (wherein R60 represents R58 or R59 as defined hereinbefore);
8) C4-5alkynylR60 (wherein R60 represents R58 or R59 as defined hereinbefore);
9) X7R40 (wherein X7 is as defined hereinbefore and R40 represents C1-3alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino);
10) C3-5alkenylR30 (wherein R30 is as defined hereinbefore);
11) C3-5alkynylR30 (wherein R30 is as defined hereinbefore);
12) C4-5alkynylX8R31 (wherein X8 and R30 are as defined hereinbefore);
13) C4-5alkynylX9R30 (wherein X9 and R30 are as defined hereinbefore);
14) C1-3alkylX10C1-3alkylR30 (wherein X10 and R30 are as defined hereinbefore);
15) R29 (wherein R29 is as defined hereinbefore); and
16) C1-3alkylX11C1-3alkylR29 (wherein X11 and R29 are as defined hereinbefore).
Advantageously R6 is selected from one of the following eleven groups:
1) C1-4alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-4alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) C2-3alkylX2COR12 (wherein X2 is as defined hereinbefore and R12 represents xe2x80x94NR14R15xe2x80x94 or xe2x80x94OR16xe2x80x94 (wherein R14, R15 and R16 which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-3alkylX3R17 (wherein X3 is as defined hereinbefore and R17 is a group selected from C1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3 through a carbon atom and which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4C2-3alkylX5R23 (wherein X4 and X5 are as defined hereinbefore) and R23 represents hydrogen or C1-2alkyl);
5) C1-4alkylR58 (wherein R58 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C1-4alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy halogeno, C1-2alkyl, C1-2hydroxyalkyl and C,2alkoxy) or C2-4alkylR59 (wherein R59 is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy); and
6) (CH2)qX6R30 (wherein X6 is as defined hereinbefore; q is an integer from 1 to 3 if X6 is a direct bond and q is 2 or 3 if X6 is other than a direct bond; and R30 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, preferably substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR36R37 and xe2x80x94NR38COR39 (wherein R36, R37, R38 and R39, which may be the same or different, each represents hydrogen or C1-2alkyl));
7) C4-5alkenylR60 (wherein R60 is as defined hereinbefore);
8) C4-5alkynylR60 (wherein R60 is as defined hereinbefore);
9) C-13alkylX10C1-3alkylR30 (wherein X10 and R30 are as defined hereinbefore);
10) R29 (wherein R29 is as defined hereinbefore); and
11) C1-3alkylX11C1-3alkylR29 (wherein X11 and R29 are as defined hereinbefore).
Preferably R6 is selected from one of the following nine groups:
1) C1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-3alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl;
3) C2-3alkylX3R17 (wherein X3 is as defined hereinbefore and R17 is a group selected from C1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3 through a carbon atom and which C1-2alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4C2-3alkylX5R23 (wherein X4 and X5 are as defined hereinbefore) and R23 represents hydrogen or C1-2alkyl);
5) C1-2alkylR58 (wherein R58 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or C2-3alkylR59 (wherein R59 is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one or two substituents selected from oxo. hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
6) (CH2)qX6R30 (wherein X6 is as defined hereinbefore; q is an integer from 1 to 3 if X6 is a direct bond and q is 2 or 3 if X6 is other than a direct bond; and R30 is a group selected from phenyl, a pyridone group, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl and pyridazinyl, preferably selected from phenyl, a pryidone group, pyridyl, imidazolyl, thiazolyl and triazolyl which group may be substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR36R37 and xe2x80x94NR38COR39 (wherein R36, R37, R38 and R39 are as defined hereinbefore);
7) C1-3alkylX10C1-3alkylR30 (wherein X10 and R30 are as defined hereinbefore);
8) R29 (wherein R29 is as defined hereinbefore); and
9) C1-3alkylX11C1-3alkylR29 (wherein X11 and R29 are as defined hereinbefore)
More preferably R6 represents 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl, 2-(N-methyl-N-4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl, 3-(4-oxidomorpholino)propyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, 3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, (1,3dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 2-(4-pyridyloxy)ethyl, 3-(4-pyridyloxy)propyl, 2-(4-pyridylamino)ethyl, 3-(4-pyridylamino)propyl, 2-(2-methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, morpholino, N-methylpiperazinyl, piperazinyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, 2-methoxyethyl, 3-methoxypropyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 3imidazol-1-yl)propyl, 3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, 2-(methylsulphinyl)ethyl, benzyl, 2-sulphamoylethyl or 2-(methylsulphonyl)ethyl. Especially R6 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, 3-(3-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
More especially R6 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl, or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
Preferably R3 is attached to Y2 or Y3.
More preferably Y2 is carbon and bears a value of R3 which is not R6xe2x80x94X1 and Y3 is carbon and bears a value of R3 which is R6xe2x80x94X1.
According to one aspect of the present invention there is provided the use of compounds of the formula Ia: 
[wherein:
R2, R3, m and n are as defined hereinbefore;
Za represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
G1a represents phenyl or 1H-indazol-6-yl; and
Y1a and Y4a each independently represents Cxe2x80x94H or nitrogen and Y2a and Y3a each represent carbon or nitrogen with the proviso that no more than two of Y1a, Y2a, Y3a and Y4a can be nitrogen at the same time;]
and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans.
According to one aspect of the present invention there is provided compounds of the formula Ib: 
[wherein:
R2, R3, m and n are as defined hereinbefore;
Zb represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
G1b represents phenyl or 1H-indazol-6-yl;
Y4b represents Cxe2x80x94H or nitrogen;
R1b represents fluoro or hydrogen; and
R5b represents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;] and salts thereof, for use as medicaments.
According to one aspect of the present invention there is provided the use of pounds of the formula Ic: 
[wherein:
G1c represents phenyl, and additionally G1c may be 1H-indazol-6-yl;
Y4c represents Cxe2x80x94H, and additionally Y4c may be nitrogen;
Rfc represents hydrogen and additionally Rfc may be fluoro;
R2c represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro;
nc is an integer from 1 to 5, and additionally nc may be 0;
Zc represents xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CH2xe2x80x94;
R1c represents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;
R3c represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or xe2x80x94NR6cR7c, (wherein R6c and R7c, which may be the same or different, each represents hydrogen or C1-3alkyl), and additionally R3c may have any of the values of R5cxe2x80x94X1cxe2x80x94 (wherein R5c and X1c are as defined hereinafter);
R4c represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, xe2x80x94NR8cR9c (wherein R8c and R9c, which may be the same or different, each represents hydrogen or C1-3alkyl), or a group R5cxe2x80x94X1cxe2x80x94 wherein X1c represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10cCOxe2x80x94, xe2x80x94CONR11cxe2x80x94, xe2x80x94SO2NR12cxe2x80x94, xe2x80x94NR13cSO2xe2x80x94 or xe2x80x94NR14cxe2x80x94 (wherein R10c, R11c, R12c, R13c and R14c each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl), and additionally X1c represents xe2x80x94OCOxe2x80x94, and R5c is selected from one of the following eight groups:
1) C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;
2) C1-5alkylX2cCOR15c (wherein X2c represents xe2x80x94Oxe2x80x94 or NR16cxe2x80x94 (wherein R16c represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R15c represents xe2x80x94NR17cR18cxe2x80x94 or xe2x80x94OR19cxe2x80x94 (wherein R17c, R18c and R19c which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl));
3) C1-5alkylX3cR20c (wherein X3c represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94NR21cCO, xe2x80x94CONR22cxe2x80x94, xe2x80x94SO2NR23cxe2x80x94, xe2x80x94NR24cSO2xe2x80x94 or xe2x80x94NR25cxe2x80x94 (wherein R21c, R22c, R23c, R24c and R25c each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R20c represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
4) C1-5alkylX4cC1-5alkylX5cR26c (wherein X4c and X5c which may be the same or different are each xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR27cCOxe2x80x94, xe2x80x94CONR28cxe2x80x94, xe2x80x94SO2NR29cxe2x80x94, xe2x80x94NR30cSO2xe2x80x94 or xe2x80x94NR31cxe2x80x94 (wherein R27c, R28c, R29c, R30c and R31c each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R26c represents hydrogen or C1-3alkyl);
5) C1-5alkylR32c (wherein R32c is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
6) (CH2)qcX6cR33c (wherein qc is an integer from 0 to 5, X6c represents a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR34cCOxe2x80x94, xe2x80x94CONR35cxe2x80x94, xe2x80x94SO2NR36cxe2x80x94, xe2x80x94NR37cSO2xe2x80x94 or xe2x80x94NR38cxe2x80x94 (wherein R34c, R35c, R36c, R37c and R38c each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R33c is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR39cR40c and xe2x80x94NR41cCOR42c (wherein R39c, R40c, R41c and R42c, which may be the same or different, each represents hydrogen or C1-4alkyl));
7) C2-6alkenylR32c (wherein R32c is as defined hereinbefore); and
8) C2-6alkenylR32c (wherein R32c is as defined hereinbefore);] and salts thereof, as medicaments.
Preferably the invention relates to the use of compounds of formula Ic for the treatment of disease states associated with angiogenesis and/or increased vascular permeablility. In one embodiment of the present invention R2c represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, trifluoromethyl, cyano, amino or nitro, preferably hydroxy, halogeno or C1-2alkyl, especially hydroxy or halogeno.
In another embodiment of the present invention one R2c is conveniently hydroxy, but advantageously one R2c substituent is meta-hydroxy and the other one or more are each selected from halogeno, methyl and methoxy.
In another embodiment of the invention the phenyl group bearing (R2c)nc is preferably of the formula IIc: 
wherein:
Rac represents hydrogen, methyl, fluoro or chloro, preferably hydrogen, fluoro or chloro, especially fluoro;
Rbc represents hydrogen, methyl, methoxy, bromo, fluoro or chloro, and additionally Rbc may be cyano;
Rcc represents hydrogen or hydroxy, especially hydroxy;
Rdc represents hydrogen, fluoro or chloro, especially hydrogen or fluoro.
Preferably in another embodiment of the invention two R2c substituents are halogeno, and the other one or more are each selected from halogeno, hydroxy and methyl. In a particular aspect of the present invention, the phenyl group bearing (R2c)nc is the 2-fluoro-5-hydroxy-4-methylphenyl group, the 4-chloro-2-fluoro-5-hydroxyphenyl group or the 4-chloro-2-fluorophenyl group, and additional values of the phenyl group bearing (R2c)nc are the 3-hydroxy-4-methylphenyl group, the 3-hydroxyphenyl group and the 4-bromo-2-fluoro-5-hydroxyphenyl group.
Preferably nc is an integer from 1 to 3, more preferably nc is 2 or 3.
Preferably Zc represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, but especially xe2x80x94NHxe2x80x94.
Preferably R1c represents hydrogen, amino, nitro or halogeno, but especially hydrogen.
Advantageously R3c represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, C1-3alkyl, C1-3alkoxy or amino, and additional advantageous values of R3c are methoxycarbonyl, 3-morpholinopropoxy and 3-morpholinopropylcarbamoyl.
Preferably R3c represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, and additional preferred values of R3c are methoxycarbonyl, 3-morpholinopropoxy and 3-morpholinopropylcarbamoyl; more preferably R3c represents hydrogen, cyano, nitro, trifluoromethyl, hydroxy, methyl or methoxy, and an additional more preferred value of R3c is methoxycarbonyl; especially R3c represents cyano or methoxy.
Preferably Rfc is hydrogen.
Preferably G1c is phenyl.
Preferably Y4c is Cxe2x80x94H.
Conveniently R4c represents halogeno, cyano, nitro, trifluoromethyl or a group R5cxe2x80x94X1cxe2x80x94 (wherein R5c and X1c are as defined hereinbefore).
Advantageously R4c represents cyano, nitro, trifluoromethyl or a group R5cxe2x80x94X1cxe2x80x94 (wherein R5c and X1c are as defined hereinbefore).
Preferably R4c represents a group R5cxe2x80x94X1cxe2x80x94 (wherein R5c and X1c are as defined hereinbefore).
Advantageously X1c represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10cCOxe2x80x94, xe2x80x94NR13cSO2xe2x80x94 or xe2x80x94NR14cxe2x80x94 (wherein R10c, R13c and R14c each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X14c represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10cCOxe2x80x94 or xe2x80x94NR13cSO2xe2x80x94 (wherein R10c and R13c each independently represents hydrogen or C1-2alkyl).
More preferably X1c represents xe2x80x94Oxe2x80x94, or xe2x80x94NHCOxe2x80x94, especially xe2x80x94Oxe2x80x94.
Advantageously X3c represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR21cCOxe2x80x94, xe2x80x94NR24cSO2xe2x80x94 or xe2x80x94NR25cxe2x80x94 (wherein R21c, R24c and R25c each independently represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X3c represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR25c (wherein R25c represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
More preferably X3c represents xe2x80x94Oxe2x80x94 or xe2x80x94NR25cxe2x80x94 (wherein R25c represents hydrogen or C1-2alkyl).
Advantageously X4c and X5c which may be the same or different each represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR31cxe2x80x94 (wherein R31c represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Preferably X4c and X5c which may be the same or different each represent xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR31cxe2x80x94 (wherein R31c represents hydrogen, C1-2alkyl or C1-2alkoxyethyl).
Advantageously X6c represents a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR38cxe2x80x94 (wherein R38c represents hydrogen, C1-2alkyl or C1-2alkoxyethyl), and an additional advantageous value of X6c is xe2x80x94NR37cSO2,
Preferably X6c represents a direct bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR38cxe2x80x94 (wherein R38c represents hydrogen or C1-2alkyl).
Conveniently R5c is selected from one of the following eight groups:
1) C1-5alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;
2) C2-3alkylX2cCOR15c (wherein X2c is as defined hereinbefore and R15c represents xe2x80x94NR17cR18cxe2x80x94 or xe2x80x94OR19cxe2x80x94 (wherein R17c, R18c and R19c which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-4alkylX3cR20c (wherein X3c is as defined hereinbefore and R20c represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-3alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
4) C2-3alkylX4cC2-3alkylX5cR26c (wherein X4c and X5c are as defined hereinbefore and R26c represents hydrogen or C1-3alkyl);
5) C1-5alkylR43c (wherein R43c is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C1-5alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy) or C2-5alkylR44c (wherein R44c is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is selected independently from O, S and N, which heterocyclic group is linked to C2-5alkyl through a nitrogen atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-3alkyl, C1-3hydroxyalkyl and C1-3alkoxy);
6) (CH2)qcX6cR33c (wherein X6c is as defined hereinbefore; qc is an integer from 0 to 4 if X6c is a direct bond and q is 0, 2 or 3 if X6c is other than a direct bond; and R33c is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, advantageously substituted with up to 2 substituents as hereinbefore defined, more preferably substituted with one substituent selected from the group of substituents as hereinbefore defined);
7) C4-5alkenylR45c (wherein R45c represents R43c or R44c as defined hereinbefore); and
8) C4-5alkynylR45c (wherein R45c represents R43c or R44c as defined hereinbefore).
Advantageously R5c is selected from one of the following eight groups:
1) C1-4alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-4alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) C2-3alkylX2cCOR15c (wherein X2c is as defined hereinbefore and R15c represents xe2x80x94NR17cR18cxe2x80x94 or xe2x80x94OR19cxe2x80x94 (wherein R17c, R18c and R19c which may be the same or different each represents hydrogen, C1-2alkyl or C1-2alkoxyethyl));
3) C2-3alkylX3cR20c (wherein X3c is as defined hereinbefore and R20c is a group selected from C1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3c through a carbon atom and which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4cC2-3alkylX5cR26c (wherein X4c and X5c are as defined hereinbefore) and R26c represents hydrogen or C1-2alkyl);
5) C1-4alkylR (wherein R43c is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C1-4alkyl through a carbon atom and which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or C2-4alkylR44c (wherein R44c is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy); and
6) (CH2)qcX6cR33c (wherein X6c is as defined hereinbefore; qc is an integer from 1 to 3 if X6c is a direct bond and qc is 2 or 3 if X6c is other than a direct bond; and R33c is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatoms selected from O, N and S, of which preferably one is N, which phenyl group, pyridone group or aromatic heterocyclic group may be substituted as hereinbefore defined, preferably substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR39cR40c and xe2x80x94NR41cCOR42c (wherein R39c, R40c, R41c and R42c which may be the same or different, each represents hydrogen or C1-2alkyl));
7) C4-5alkenylR45c (wherein R45c is as defined hereinbefore); and
8) C4-5alkynylR45c (wherein R45c is as defined hereinbefore).
Preferably R5c is selected from one of the following six groups:
1) C1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C2-3alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;
2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-NN,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl;
3) C2-3alkylX3cR20c (wherein X3c is as defined hereinbefore and R20c is a group seleceted from C1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X3c from hydroxy, halogeno and C1-2alkoxy and oxo, and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy);
4) C2-3alkylX4cC2-3alkylX5cR26c (wherein X4c and X5c are as defined hereinbefore) and R26c represents hydrogen or C1-2alkyl);
5) C1-2alkylR43c (wherein R43c is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy) or C2-3alkylR44c (wherein R44c is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one substituent, or two substitutents, selected from oxo, hydroxy, halogeno, C1-2alkyl, C1-2hydroxyalkyl and C1-2alkoxy); and
6) (CH2)qcX6cR33c (wherein X6c is as defined hereinbefore; qc is an integer from 1 to 3 if X6c is a direct bond and qc is 2, or 3, if X6c is other than a direct bond; and R33c is a group selected from phenyl, a pyridone group, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl and pyridazinyl, preferably selected from phenyl, a pryidone group, pyridyl, imidazolyl, thiazolyl and triazolyl which group may be substituted with one substituent selected from hydroxy, halogeno, C1-2alkyl, C1-2alkoxy, C1-2hydroxyalkyl, C1-2hydroxyalkoxy, carboxy, cyano, xe2x80x94CONR39cR40c and NR41cCOR42c (wherein R39c R40c, R41c and R42c are as defined hereinbefore).
More preferably R5c represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl, and additional more preferred values for R5c are 3-(3-pyridyl)propyl, 2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl, 2-((N-methyl-N-4-pyridyl)amino)ethyl, 2-(4-oxidomorpholino)ethyl, 3-(4-oxidomorpholino)propyl, 3-(4-oxo-1,4-dihydro-1-pyridyl)propyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 3-(4-pyridyloxy)propyl, 3-(4-pyridylamino)propyl, 2-(2-methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, 3-(imidazol-1-yl)propyl, 3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl and 3-(methylsulphonyl)propyl.
Especially R5c represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl or 2-(4-oxo-1,4-dihydro 1-pyridyl)ethyl, and an additional value for R5c is 3-(3-pyridyl)propyl.
More especially R5c represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, benzyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl or 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl.
The present invention also provides compounds of the formula Id: 
(wherein Rfc, R1c, R2c, R3c, R4c, Y4c, G1c and nc are as defined hereinbefore with the proviso that where R4c is chlorine at least one R2c is hydroxy), and salts thereof.
Thus where R4c is chlorine the moiety IId: 
may represent any substituted phenyl group within the definitions of R2c and nc as defined hereinbefore for formula I, provided that the phenyl moiety carries at least one hydroxy substituent.
Advantageously R4c is other than chlorine, preferably other than halogeno and especially other than hydrogen, halogeno or C1-3alkyl.
Preferably R4c is a group R5cxe2x80x94X1cxe2x80x94 wherein R5c and X1c are as defined hereinbefore with the proviso that R5c is other than an unsubstituted C1-5alkyl group and other than a C1-5alkyl group substituted with one or more fluorine atoms.
Preferred compounds are:
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline,
4-(4-chloro-2-fluoroanilino)-7-(3-(dimethylamino)propoxy)-6-methoxyquinoline,
6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)quinoline,
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-([1,2,4]-triazol-1-yl)ethoxy)quinoline,
4-(4-bromo-2-fluoro-5-hydroxyanilino)-7-chloroquinoline,
7-chloro-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinoline,
6,7-dimethoxy-4-(3-hydroxyanilino)quinoline,
4-(4-chloro-2-fluorophenoxy)-6,7-dimethoxyquinoline,
4-(4-chloro-2-fluoroanilino)-7-(3-hydroxypropoxy)-6-methoxyquinoline,
4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinoline,
7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinoline and
4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(N-[3-morpholinopropyl]carbamoyl)quinoline and salts thereof, particularly hydrochloride salts thereof.
More preferred compounds are:
4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxy-6-methoxycarbonylquinoline,
4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(3-morpholinopropoxy)quinoline,
6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline,
6,7dimethoxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline,
6,7-dimethoxy-3-fluoro-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-7-ethoxy-6-methoxyquinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(3-pyridyl)propoxy)quinoline,
6,7-dimethoxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinoline,
4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline,
4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinoline,
4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline,
6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(3-morpholinopropoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline,
4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(4-pyridylmethoxy)quinoline,
4-(4-chloro-2-fluoro-5-hvdroxyanilino)-6-methoxy-7-(2-morpholinoethoxy)quinoline,
6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline,
7-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline and
4-(4-chloro-2-fluoroanilino)-7-(2-hydroxyethoxy)-6-methoxyquinoline and salts thereof, particularly hydrochloride salts thereof.
Especially preferred compounds are:
6-cyano-4-(3-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline,
7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline,
6-cyano-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-7-(2-methoxyethoxy)quinoline,
7-benzyloxy-4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline
4-(4-bromo-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinoline,
4-(4-chloro-2-fluoroanilino)-6-cyano-7-(2-methoxyethoxy)quinoline,
4-(4-chloro-2-fluoroanilino)-6-cyano-7-(3-morpholinopropoxy)quinoline,
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline and
4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline and salts thereof, particularly hydrochloride salts thereof.
In a particular aspect of the present invention preferred compounds are:
6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline,
4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline,
4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(3-morpholinopropoxy)quinoline,
6-cyano-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-7-(2-methoxyethoxy)quinoline,
4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline,
7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinoline,
4-(27fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline,
4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6,7-dimethoxyquinoline, and salts thereof, particularly hydrochloride salts thereof.
For the avoidance of doubt it is to be understood that where in this specification a group is described as defined hereinbefore this encompasses the first occurring and broadest definition as well as each and all of the preferred definitions for that group. For example, for compounds of formula I, n is defined as an integer from 0 to 5 but n is preferably an integer from 1 to 3, more preferably 2 or 3. Thus references in the specification to n as being xe2x80x9cdefined hereinbeforexe2x80x9d are to be understood as references to not only the broadest prior definition of n, but also to incorporate the stated preferences for the definition of n.
In this specification unless stated otherwise the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. An analogous convention applies to other generic terms. Unless otherwise stated the term xe2x80x9calkylxe2x80x9d advantageously refers to chains with 1-6 carbon atoms, preferably 1-4 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d as used herein, unless stated otherwise includes xe2x80x9calkylxe2x80x9dxe2x80x94Oxe2x80x94 groups in which xe2x80x9calkylxe2x80x9d is as hereinbefore defined. The term xe2x80x9carylxe2x80x9d as used herein unless stated otherwise includes reference to a Case aryl group which may, if desired, carry one or more substituents selected from halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (wherein alkyl and alkoxy are as hereinbefore defined). The term xe2x80x9caryloxyxe2x80x9d as used herein unless otherwise stated includes xe2x80x9carylxe2x80x9dxe2x80x94Oxe2x80x94groups in which xe2x80x9carylxe2x80x9d is as hereinbefore defined. The term xe2x80x9csulphonyloxyxe2x80x9d as used herein refers to alkylsulphonyloxy and arylsulphonyloxy groups in which xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are as hereinbefore defined. The term xe2x80x9calkanoylxe2x80x9d as used herein unless otherwise stated includes alkylCxe2x95x90O groups in which xe2x80x9calkylxe2x80x9d is as defined hereinbefore, for example ethanoyl refers to CH3Cxe2x95x90O. In this specification unless stated otherwise the term xe2x80x9calkenylxe2x80x9d includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl are specific for the straight chain version only. Unless otherwise stated the term xe2x80x9calkenylxe2x80x9d advantageously refers to chains with 2-6 carbon atoms, preferably 4-5 carbon atoms. In this specification unless stated otherwise the term xe2x80x9calkynylxe2x80x9d includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl are specific for the straight chain version only.
Unless otherwise stated the term xe2x80x9calkynylxe2x80x9d advantageously refers to chains with 2-6 carbon atoms, preferably 4-5 carbon atoms.
Within the present invention it is to be understood that a compound of the formula I or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits VEGF receptor tyrosine kinase activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
It is also to be understood that certain compounds of the formula I and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit VEGF receptor tyrosine kinase activity.
For the avoidance of any doubt, it is to be understood that when X1 is, for example, a group of formula xe2x80x94NR7COxe2x80x94, it is the nitrogen atom bearing the R7 group which is attached to the heterocyclic/quinoline ring and the carbonyl (CO) group is attached to R6, whereas when X1 is, for example, a group of formula xe2x80x94CONR8xe2x80x94, it is the carbonyl group which is attached to the heterocyclic/quinoline ring and the nitrogen atom bearing the R8 group is attached to R6.
A similar convention applies to the other two atom X1 linking groups such as xe2x80x94NR10SO2xe2x80x94, and xe2x80x94SO2NR9xe2x80x94. When X1 is xe2x80x94NR11xe2x80x94 it is the nitrogen atom bearing the R11 group which is linked to the heterocyclic/quinoline ring and to R6. When X1 is xe2x80x94OCOxe2x80x94 it is the carbonyl group which is is attached to the heterocyclic/quinoline ring and the oxy group is attached to R6. Analogous conventions apply to groups X2-10. It is further to be understood that when X2 represents xe2x80x94NR13xe2x80x94 and R13 is C1-3alkoxyC2-3alkyl it is the C2-3alkyl moiety which is linked to the nitrogen atom of X2 and an analogous convention applies to other groups.
For the avoidance of any doubt, it is to be understood that when R30 carries a C1-4aminoalkyl substituent it is the C1-4alkyl moiety which is attached to R30 whereas when R30 carries a C1-4alkylamino substituent it is the amino moiety which is attached to R30 and an analogous convention applies to other groups.
The present invention relates to the use of the compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form such salts. Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid. In addition where the compounds of formula I are sufficiently acidic, pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
A compound of the formula Id, or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Application, Publication No. 0326330 and U.S. Pat. No. 3,936,461. Such processes, are provided as a further feature of the invention and are as described hereinafter. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
Thus the following processes (a) to (f) and (i) to (vi) constitute further features of the present invention.
(a) Compounds of the formula I and salts thereof may be prepared by the reaction of a compound of the formula III: 
(wherein R1, R3, Y1, Y2, Y3, Y4 and m are as defined hereinbefore and L1 is a displaceable moiety), with a compound of the formula IV: 
(wherein G1, R2 and n are as defined hereinbefore) whereby to obtain compounds of the formula I and salts thereof. A convenient displaceable moiety L1 is, for example, a halogeno, alkoxy (preferably C1-4alkoxy), aryloxy or sulphonyloxy group, or an alkylthio group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group, or a methylthio group.
The reaction is advantageously effected in the presence of either an acid or a base. Such an acid is, for example, an anhydrous inorganic acid such as hydrogen chloride. Such a base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. Alternatively such a base is, for example, an alkali metal hydride, for example sodium hydride, or an alkali metal or alkaline earth metal amide, for example sodium amide or sodium bis(trimethylsilyl)amide. The reaction is preferably effected in the presence of an inert solvent or diluent, for example an alkanol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently effected at a temperature in the range, for example, 10 to 150xc2x0 C., preferably in the range 40 to 120xc2x0 C.
The compound of the invention may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of the formula Hxe2x80x94L1wherein L1 has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a base as defined hereinbefore using a conventional procedure.
(b) Where the group of formula II: 
(wherein Ra, Rb, Rc and Rd are as defined hereinbefore) represents a phenyl group carrying one or more hydroxy groups, a compound of the formula I and salts thereof can be prepared by the deprotection of a compound of formula V: 
(wherein n, Y1, Y2, Y3, Y4, R1, R2, R3, m and Z are as hereinbefore defined, P represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 5 equal to the number of protected hydroxy groups and such that n-p1 is equal to the number of R2 substituents which are not protected hydroxy). The choice of phenolic hydroxy protecting group P is within the standard knowledge of an organic chemist, for example those included in standard texts such as xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d T. W. Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, including ethers (for example, methyl, methoxymethyl, allyl and benzyl), silyl ethers (for example, t-butyldiphenylsilyl and t-butyldimethylsilyl), esters (for example, acetate and benzoate) and carbonates (for example, methyl and benzyl). The removal of such a phenolic hydroxy protecting group may be effected by any of the procedures known for such a transformation, including those reaction conditions indicated in standard texts such as that indicated hereinbefore, or by a related procedure. The reaction conditions preferably being such that the hydroxy derivative is produced without unwanted reaction at other sites within the starting or product compounds. For example, where the protecting group P is acetate, the transformation may conveniently be effected by treatment of the quinoline derivative with a base as defined hereinbefore and including ammonia, and its mono and di-alkylated derivatives, preferably in the presence of a protic solvent or co-solvent such as water or an alcohol, for example methanol or ethanol. Such a reaction can be effected in the presence of an additional inert solvent or diluent as defined hereinbefore and at a temperature in the range 0 to 50xc2x0 C., conveniently at about 20xc2x0 C.
(c) Production of those compounds of formula I and salts thereof wherein a substituent R3 is R6xe2x80x94X1xe2x80x94 and wherein X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR11xe2x80x94 can be achieved by the reaction, conveniently in the presence of a base as defined hereinbefore, of a compound of the formula VI: 
(wherein n, X1, Y1, Y2, Y3, Y4, G1, R1, R2, R3, Z and m are as hereinbefore defined) with a compound of formula VII:
R6xe2x80x94L1xe2x80x83xe2x80x83(VII)
(wherein R6 and L1 are as hereinbefore defined); L1 is a displaceable moiety for example a halogeno or sulphonyloxy group such as a bromo or methanesulphonyloxy group. The reaction is preferably effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 150xc2x0 C., conveniently at about 50xc2x0 C.
(d) Compounds of the formula I and salts thereof wherein a substituent R3 is R6xe2x80x94X1xe2x80x94 and wherein R6 is C1-5alkylR61, [wherein R61 is selected from one of the following two groups:
1) X11R17 (wherein X11 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR62COxe2x80x94, xe2x80x94NR63SO2xe2x80x94 or xe2x80x94NR64xe2x80x94 (wherein R62, R63 and R64, each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R17 is as defined hereinbefore); and
2) X12C1-5alkylX5R23 (wherein X12 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2, xe2x80x94NR65COxe2x80x94, xe2x80x94NR66SO2xe2x80x94 or xe2x80x94NR67xe2x80x94 (wherein R65, R66 and R67, each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and X5 and R23 are as defined hereinbefore);] may be prepared by reacting a compound of the formula VIII: 
(wherein L1, X1, G1, Y1, Y2, Y3, Y4, R1, R2, R3, Z, m and n are as hereinbefore defined and R68 is C1-5alkyl) with a compound of the formula IX:
R61xe2x80x94Hxe2x80x83xe2x80x83(IX)
(wherein R61 is as defined hereinbefore) to give a compound of the formula I. The reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range, for example 0 to 150xc2x0 C., conveniently at about 50xc2x0 C.
Compounds of the formula I wherein a substituent R3 is R6xe2x80x94X1xe2x80x94 and wherein R6 is C2-5alkylR59, (wherein R59 is as defined hereinbefore), may be prepared by reacting a compound of formula VIII (wherein R61 is C1-5alkyl) with a compound of the formula IXa:
R59xe2x80x94Hxe2x80x83xe2x80x83(IXa)
(wherein R59 is as defined hereinbefore) to give a compound of the formula I. The reaction may conveniently be effected in the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), and at a temperature in the range, for example 0 to 150xc2x0 C., conveniently at about 50xc2x0 C.
(e) The production of those compounds of the formula I and salts thereof wherein a substituent R3 is represented by xe2x80x94NR4R5, where one or both of R4 and R5 are C1-3alkyl, may be effected by the reaction of compounds of formula I wherein the substituent R3 is an amino group and an alkylating agent, preferably in the presence of a base as defined hereinbefore. Such alkylating agents are C1-3alkyl moieties bearing a displaceable moiety as defined hereinbefore such as C1-3alkyl halides for example C1-3alkyl chloride, bromide or iodide. The reaction is preferably effected in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)) and at a temperature in the range, for example, 10 to 100xc2x0 C., conveniently at about ambient temperature.
(f) The production of compounds of formula I and salts thereof wherein one or more of the substituents R2 and R3 is an amino group may be effected by the reduction of a corresponding compound of formula I wherein the substituent(s) at the corresponding position(s) of the heterocyclic/quinoline and/or heterocyclic/phenyl ring is/are a nitro group(s). The reduction of the nitro group(s) may conveniently be effected by any of the procedures known for such a transformation. The reduction may be carried out, for example, by the hydrogenation of a solution of the nitro compound in the presence of an inert solvent or diluent as defined hereinbefore in the presence of a metal effective to catalyse hydrogenation reactions such as palladium or platinum. A further reducing agent is, for example, an activated metal such as activated iron (produced for example by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the reduction may be effected by heating the nitro compound and the activated metal in the presence of a solvent or diluent such as a mixture of water and alcohol, for example methanol or ethanol, to a temperature in the range, for example 50 to 150xc2x0 C., conveniently at about 70xc2x0 C. The production of a compound of formula I and salts thereof wherein the substituent(s) at the corresponding position(s) of the heterocyclic/quinoline and/or heterocyclic/phenyl ring is/are a nitro group(s) may be effected by the processes described hereinbefore and hereinafter in processes (a-d) and (i-vi) using a compound selected from the compounds of the formulae (I-XXIII) in which the substituent(s) at the corresponding position(s) of the heterocyclic/quinoline and/or heterocyclic/phenyl ring is/are a nitro group(s).
(i) Such compounds of formula III and salts thereof in which L1 is halogeno may for example be prepared by halogenating a compound of the formula X: 
(wherein m, R1, R3, Y1, Y2, Y3 and Y4 are as hereinbefore defined).
Convenient halogenating agents include inorganic acid halides, for example thionyl chloride, phosphorus(III)chloride, phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenation reaction is conveniently effected in the presence of an inert solvent or diluent such as for example a halogenated solvent such as methylene chloride, trichloromethane or carbon tetrachloride, or an aromatic hydrocarbon solvent such as benzene or toluene. The reaction is conveniently effected at a temperature in the range, for example 10 to 150xc2x0 C., preferably in the range 40 to 100xc2x0 C.
The compounds of formula X and salts thereof wherein one or more of Y1, Y2, Y3 and Y4 are nitrogen, may for example, be prepared by any of the known procedures for making azaquinolones, such as procedures analogous to those described in xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d Volume 2, Naphthyridine Chemistry, Katritsky and Rees, 1984; DE 2423650; Cubza, Synthesis 1974, 809; Barlin et al., Aust. J. Chem. 1984, 37 1065; WO 9313097 A1; WO 9500511 A1; Hirao et al., Bull. Chem. Soc. Jpn. 1973, 46, 1826; Carboni et al., Gazz. Chim. Ital. 1972, 102, 253 and 264; Carboni et al., Gazz Chim. Ital. 1971, 101, 129 and 133 and 137; Bowie J. Chem. Soc. Perk Trans I, 1972, 1106; Brown J. Org Chem. 1965, 30, 1607; Quequiner et al., Can. J. Chem. 1992, 70, 2828; Reynolds et al., J. Chem. Soc. Perk Trans II, 1988, 4, 551; Nagai et al JP 51054596; Sato et al JP 51054593.
The compounds of formula X and salts thereof may for example be prepared by reacting a compound of the formula XI: 
with a compound of the formula XII:
R6xe2x80x94X1xe2x80x94Hxe2x80x83xe2x80x83(XII)
(wherein R1, R3, m, Y1, Y2, Y3, Y4, L1, R6 and X1 are as hereinbefore defined). The reaction may conveniently be effected the presence of a base (as defined hereinbefore in process (a)) and advantageously in the presence of an inert solvent or diluent (as defined hereinbefore in process (a)), advantageously at a temperature in the range, for example 10 to 200xc2x0 C., preferably in the range 100 to 150xc2x0 C.
The compounds of formula X and salts thereof may also be prepared by cyclising a compound of the formula XIII: 
(wherein Y1, Y2, Y3, Y4, R3 and m are as hereinbefore defined,) whereby to form a compound of formula X or salt thereof. The cyclisation may be effected by heating a compound of the formula XIII in the presence of an inert solvent or diluent such as an ether, for example diphenyl ether, at an elevated temperature, preferably in the range 200 to 300xc2x0 C.
Compounds of formula XIII may for example be prepared by reacting a compound of the formula XIV: 
with a compound of the formula XV: 
(wherein Y1, Y2, Y3, Y4, R3 and m are as hereinbefore defined and A1 is an alkoxy (preferably C1-4alkoxy) group). The reaction may conveniently be effected in the presence of an alcohol as solvent, such as ethanol and advantageously at a temperature in the range for example 20 to 100xc2x0 C., preferably in the range 50 to 100xc2x0 C.
The compounds of formula III and salts thereof may also be prepared for example by reacting a compound of the formula XVI: 
(wherein Y1, Y2, Y3, Y4, R1, R3, m and X1 are as hereinbefore defined, with the proviso that X1 is not xe2x80x94CH2xe2x80x94, and L2 represents a displaceable protecting moiety) with a compound of the formula VII as hereinbefore defined, whereby to obtain a compound of formula III in which L1 is represented by L2.
A compound of formula XVI is conveniently used in which L2 represents a chloro group or a phenoxy group which may if desired carry up to 5 substituents, preferably up to 2 substituents, selected from halogeno, nitro and cyano. The reaction may be conveniently effected under conditions as described for process (c) hereinbefore.
The compounds of formula XVI and salts thereof as hereinbefore defined may for example be prepared by deprotecting a compound of the formula XVII: 
(wherein R1, R3, m, Y1, Y2, Y3, Y4, P, X1 and L2 are as hereinbefore defined). Deprotection may be effected by techniques well known in the literature, for example where P represents a benzyl group deprotection may be effected by hydrogenolysis or by treatment with trifluoroacetic acid.
One compound of formula III may if desired be converted into another compound of formula III in which the moiety L1 is different. Thus for example a compound of formula III in which L1 is other than halogeno, for example optionally substituted phenoxy, may be converted to a compound of formula III in which L1 is halogeno by hydrolysis of a compound of formula III (in which L1 is other than halogeno) to yield a compound of formula X as hereinbefore defined, followed by introduction of halide to the compound of formula X, thus obtained as hereinbefore defined, to yield a compound of formula III in which L1 represents halogeno.
(ii) The compounds of formula V and salts thereof, constitute a further feature of the present invention, and may for example be prepared by the reaction of a compound of formula III as hereinbefore defined with a compound of the formula XVIII: 
(wherein R2, n, Z, p1 and P are as hereinbefore defined). The reaction may for example be effected as described for process (a) hereinbefore.
The compounds of formula V and salts thereof may also be prepared by reacting a compound of formula XIX: 
(wherein R1, R2, R3, Z, X1, Y1, Y2, Y3, Y4, P, p1, m and n are as hereinbefore defined with the proviso that X1 is not xe2x80x94CH2xe2x80x94) with a compound of the formula VII as hereinbefore defined. The reaction may for example be effected as described for process (c) hereinbefore.
Compounds of the formula XIX and salts thereof constitute another feature of the present invention and may be made by reacting compounds of the formulae XVII and XVIII as hereinbefore defined, under conditions described in (a) hereinbefore, to give a compound of formula XX: 
(wherein R1, R2, R3, Z, Y1, Y2, Y3, Y4, P, X1, m, p1 and n are as hereinbefore defined) and then deprotecting the compound of formula XX for example as described in (i) above. Compounds of the formula XX as hereinbefore defined and salts thereof constitute a further feature of the present invention.
(iii) Compounds of the formula VI as hereinbefore defined and salts thereof constitute a further feature of the present invention and may be made by deprotecting the compound of formula XXI: 
(wherein R1, R2, R3, Z, Y1, Y2, Y3, Y4, G1, P, X1, m and n are as hereinbefore defined) by a process for example as described in (i) above.
Compounds of the formula XXI and salts thereof may be made by reacting compounds of the formulae XVII and IV as hereinbefore defined, under the conditions described in (a) hereinbefore, to give a compound of the formula XXI or salt thereof.
(iv) Compounds of the formula VIII as defined hereinbefore and salts thereof constitute a further feature of the present invention and may for example be made by the reaction of a compound of formula VI as defined hereinbefore with a compound of the formula XXII:
L1xe2x80x94R68xe2x80x94L1xe2x80x83xe2x80x83(XXII)
(wherein L1 and R68 are as hereinbefore defined) to give a compound of the formula VIII. The reaction may be effected for example by a process as described in (c) above.
Compounds of the formula VIII and salts thereof may also be made for example by deprotecting a compound of the formula XXIII: 
(wherein L1, R68, X1, R1, R2, R3, Z, Y1, Y2, Y3, Y4, G1, P, m, n and p1 are as defined hereinbefore) by a process for example as described in (b) above.
Compounds of the formula XXIII as hereinbefore defined and salts thereof constitute a further feature of the present invention and may be made for example by reacting compounds of the formulae XIX and XXII as defined hereinbefore, under the conditions described in (c) above.
(v) Compounds of the formula IV may be prepared by any known procedure for making substituted phenyl or substituted or unsubstituted heteroaromatic groups. In particular aminoindazoles may be made according to methods analogous to those described in Cockerill et al. WO 970369 Al. Davies, J. Chem. Soc., 1955, 2412-2418; Pernot et al., Bull. Soc. Chim. France, 1958, 152,156; Pfannstiel et al., Chem. Bericht., 1942, 75, 1096; U.S. Pat. No. 2,787,515, 1955; CH 543515, 1973; Boyer et al., J. Chem. Res. miniprint 1990, 11, 3601; Boyer et al., Heterocycles 1995, 41, 487.
(vi) Compounds of the formula I and salts thereof wherein R1 is fluoro, may be prepared by an analogous procedure to that described in Example 14.
When a pharmaceutically acceptable salt of a compound of the formula Id is required, it may be obtained, for example, by reaction of said compound with, for example, an acid using a conventional procedure, the acid having a pharmaceutically acceptable anion.
Many of the intermediates defined herein are novel, for example, those of the formulae V, VI, VIII, XIX, XX and XXIII and these are provided as a further feature of the invention.
Intermediates of the formulae III, X and XXI are also provided as a further feature of the invention.
The identification of compounds which potently inhibit the tyrosine kinase activity associated with the VEGF receptors such as Flt and/or KDR and which inhibit angiogenesis and/or increased vascular permeability is desirable and is the subject of the present invention. These properties may be assessed, for example, using one or more of the procedures set out below:
This assay determines the ability of a test compound to inhibit tyrosine kinase activity. DNA encoding VEGF or epidermal growth factor (EGF) receptor cytoplasmic domains may be obtained by total gene synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. These may then be expressed in a suitable expression system to obtain polypeptide with tyrosine kinase activity. For example VEGF and EGF receptor cytoplasmic domains, which were obtained by expression of recombinant protein in insect cells, were found to display intrinsic tyrosine kinase activity. In the case of the VEGF receptor Flt (Genbank accession number X51602), a 1.7 kb DNA fragment encoding most of the cytoplasmic domain, commencing with methionine 783 and including the termination codon, described by Shibuya et al (Oncogene, 1990, 5: 519-524), was isolated from cDNA and cloned into a baculovirus transplacement vector (for example pAcYM1 (see The Baculovirus Expression System: A Laboratory Guide, L. A. King and R. D. Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from Invitrogen Corporation)). This recombinant construct was co-transfected into insect cells (for example Spodoptera frugiperda 21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus. (Details of the methods for the assembly of recombinant DNA molecules and the preparation and use of recombinant baculovirus can be found in standard texts for example Sambrook et al, 1989, Molecular cloningxe2x80x94A Laboratory Manual, 2nd edition. Cold Spring Harbour Laboratory Press and O""Reilly et al, 1992, Baculovirus Expression Vectorsxe2x80x94A Laboratory Manual, W. H. Freeman and Co, New York). For other tyrosine kinases for use in assays, cytoplasmic fragments starting from methionine 806 (KDR, Genbank accession number L04947) and methionine 668 (EGF receptor, Genbank accession number X00588) may be cloned and expressed in a similar manner.
For expression of cFlt tyrosine kinase activity, Sf21 cells were infected with plaque-pure cFlt recombinant virus at a multiplicity of infection of 3 and harvested 48 hours later. Harvested cells were washed with ice cold phosphate buffered saline solution (PBS) (10 mM sodium phosphate pH7.4, 138 mM sodium chloride, 2.7 mM potassium chloride) then resuspended in ice cold HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodium chloride, 10% v/v glycerol, 1% v/v Triton X100, 1.5 mM magnesium chloride, 1 mM ethylene glycol-bis(xcex2aminoethyl ether) N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphnyl fluoride); the PMSF is added just before use from a freshly-prepared 100 mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. The suspension was centrifuged for 10 minutes at 13,000 rpm at 4xc2x0 C., the supernatant (enzyme stock) was removed and stored in aliquots at xe2x88x9270xc2x0 C. Each new batch of stock enzyme was titrated in the assay by dilution with enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM sodium orthovanadate, 0.1% v/v Triton X100, 0.2 mM dithiothreitol). For a typical batch, stock enzyme is diluted 1 in 2000 with enzyme diluent and 50 xcexcl of dilute enzyme is used for each assay well.
A stock of substrate solution was prepared from a random copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at xe2x88x9220xc2x0 C. and diluted 1 in 500 with PBS for plate coating.
On the day before the assay 100xcexcl of diluted substrate solution was dispensed into all wells of assay plates (Nunc maxisorp 96-well immunoplates) which were sealed and left overnight at 4xc2x0 C.
On the day of the assay the substrate solution was discarded and the assay plate wells were washed once with PBST (PBS containing 0.05% v/v Tween 20) and once with 50 mM Hepes pH7.4.
Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25xcexcl of diluted compound was transferred to wells in the washed assay plates. xe2x80x9cTotalxe2x80x9d control wells contained 10% DMSO instead of compound. Twenty five microlitres of 40 mM manganese(II)chloride containing 8 xcexcM adenosine-5xe2x80x2-triphosphate (ATP) was added to all test wells except xe2x80x9cblankxe2x80x9d control wells which contained manganese(II)chloride without ATP. To start the reactions 50 xcexcl of freshly diluted enzyme was added to each well and the plates were incubated at room temperature for 20 minutes. The liquid was then discarded and the wells were washed twice with PBST. One hundred microlitres of mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology Inc. product 05-321), diluted 1 in 6000 with PBST containing 0.5% w/v bovine serum albumin (BSA), was added to each well and the plates were incubated for 1 hour at room temperature before discarding the liquid and washing the wells twice with PBST. One hundred microlitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody (Amersham product NXA 931), diluted 1 in 500 with PBST containing 0.5% w/v BSA, was added and the plates were incubated for 1 hour at room temperature before discarding the liquid and washing the wells twice with PBST. One hundred microlitres of 2,2xe2x80x2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution, freshly prepared using one 50 mg ABTS tableoehringer 1204 521) in 50 ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodium perborate (made with 1 phosphate citrate buffer with sodium perborate (PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added to each well. Plates were then incubated for 20-60 minutes at room temperature until the optical density value of the xe2x80x9ctotalxe2x80x9d control wells, measured at 405 nm using a plate reading spectrophotometer, was approximately 1.0. xe2x80x9cBlankxe2x80x9d (no ATP) and xe2x80x9ctotalxe2x80x9d (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibition of enzyme activity.
This assay determines the ability of a test compound to inhibit the growth factor-stimulated proliferation of human umbilical vein endothelial cells (HUVEC).
HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v foetal calf serum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/v FCS+3xcexcg/ml heparin 1 xcexcg/ml hydrocortisone, at a concentration of 1000 cells/well in 96 well plates. After a minimum of 4 hours they were dosed with the appropriate growth factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml or b-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4 days at 37xc2x0 C. with 7.5% CO2. On day 4 the cultures were pulsed with 1 xcexcCi/well of tritiated-thymidine (Amersham product TRA 61) and incubated for 4 hours. The cells were harvested using a 96-well plate harvester (Tomtek) and then assayed for incorporation of tritium with a Beta plate counter. Incorporation of radioactivity into cells, expressed as cpm, was used to measure inhibition of growth factor-stimulated cell proliferation by compounds.
This test measures the capacity of compounds to reduce the acute increase in uterine weight in rats which occurs in the first 4-6 hours following oestrogen stimulation. This early increase in uterine weight has long been known to be due to oedema caused by increased permeability of the uterine vasculature and recently Cullinan-Bove and Koos (Endocrinology, 1993,133:829-837) demonstrated a close temporal relationship with increased expression of VEGF mRNA in the uterus. We have found that prior treatment of the rats with a neutralising monoclonal antibody to VEGF significantly reduces the acute increase in uterine weight, confirming that the increase in weight is substantially mediated by VEGF.
Groups of 20 to 22-day old rats were treated with a single subcutaneous dose of oestradiol benzoate (2.5 xcexcg/rat) in a solvent, or solvent only. The latter served as unstimulated controls. Test compounds were orally administered at various times prior to the administration of oestradiol benzoate. Five hours after the administration of oestradiol benzoate the rats were humanely sacrificed and their uteri were dissected, blotted and weighed. The increase in uterine weight in groups treated with test compound and oestradiol benzoate and with oestradiol benzoate alone was compared using a Student T test. Inhibition of the effect of oestradiol benzoate was considered significant when p less than 0.05.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier which is in one of the following forms: (i) a tablet, lozenge or capsule suitable for oral administration; (ii) a parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion; (iii) an ointment, patch or cream for topical administration; or (iv) a suppository for rectal administration. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square metre body area of the animal, i.e. approximately 0.1-100 mg/kg. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
According to a further aspect of the present invention there is provided a compound of the formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that compounds of the present invention inhibit VEGF receptor tyrosine kinase activity and are therefore of interest for their antiangiogenic effects and/or their ability to cause a reduction in vascular permeability.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinbefore.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to the antiangiogenic and/or vascular permeability reducing treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic agent:
(i) other antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example linomide, inhibitors of integrin xcex1vxcex23 function, angiostatin, razoxin, thalidomide);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5xcex1-dihydroreductase (for example finasteride), anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example EGF, FGFs, platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); and
(iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan).
As stated above the compounds defined in the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects. Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi""s sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation. In particular such compounds of the invention are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast. prostate, lung, vulva and skin.
In addition to their use in therapeutic medicine, the compounds of formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of VEGF receptor tyrosine kinase activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
It is to be understood that where the term xe2x80x9cetherxe2x80x9d is used anywhere in this specification it refers to diethyl ether.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
[(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration:
(ii) operations were carried out at ambient temperature, that is in the range 18-25xc2x0 C. and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Koffler hot plate apparatus.
(vi) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet;
(vii) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or NMR analysis;
(viii) petroleum ether refers to that fraction boiling between 40-60xc2x0 C.
(ix) the following abbreviations have been used:
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
TFA trifluoroacetic acid
NMP 1-methyl-2-pyrrolidinone
DMAP 4-dimethylaminopyridine]